In 1540, the Spanish explorer Hernando De Soto penetrated to the Arkansas River and perhaps well into present-day southeastern Missouri, which was then populated by various Native American tribes, including the Osage.

Under pressure from a constantly advancing white settlement, the Native Americans gradually retreated westward.

The area of southeastern Missouri was noted for its level swampy lowlands, subject to the seasonal flooding of the Mississippi River, which had resulted in extremely fertile soil.

By 1820 American pioneers, many migrating from the southern states, had settled most of the present counties of southeastern Missouri.

Cotton was cultivated through the 19th century, and the planters depended on enslaved African-American workers before the Civil War and freedmen afterward.

During the late 19th and early 20th centuries, violence increased against black Americans as the state disfranchised minority voters and enforce the Jim Crow segregation laws.

Sam Fields and Robert Coleman were lynched in Charleston on July 3, 1910, allegedly for committing murder and robbery.

Following the clearing of the timber, the state assisted in the construction of levees, forming drainage districts to redevelop the land.

As hundreds of miles of levees and dikes were constructed within the Little River Drainage District, thousands of acres of land were drained and "reclaimed" for agricultural use.

The reclaimed land, highly fertile due to centuries of flooding from the Mississippi River, was cultivated for cotton, corn, and wheat.

With changes in agriculture and mechanization requiring fewer workers, the number of jobs have declined, as has county population.

Voters in Mississippi County generally adhere to socially and culturally conservative principles but are more moderate or populist on economic issues, typical of what was formerly considered the white conservative Dixiecrat philosophy of southern Democrats, before African Americans regained the power to vote.

The proposition strongly passed every single county in Missouri, with 75.94 percent voting in favor as the minimum wage was increased to $6.50 an hour in the state.

During the 2008 presidential primary, voters in Mississippi County from both political parties supported candidates who finished in second place in the state at large and nationally.

Senator Hillary Clinton (D-New York) received more votes, a total of 1,094, than any candidate from either party in Mississippi County during the 2008 presidential primary.